What does it mean to have low Insulin-like Growth Factor-1 (IGF-1) levels?

What Low IGF-1 Means

Low IGF-1 levels indicate either inadequate growth hormone (GH) production, peripheral resistance to GH action, or secondary suppression from malnutrition, chronic illness, hypothyroidism, liver disease, or certain medications—each requiring distinct diagnostic and therapeutic approaches.

Primary Diagnostic Considerations

Low IGF-1 must be interpreted in the context of age, sex, pubertal stage (Tanner stage), and clinical presentation, as normal ranges vary significantly across the lifespan 1.

Growth Hormone Deficiency (GHD)

• In adults with documented pituitary disease and two or more additional pituitary hormone deficiencies, an IGF-1 level <84 μg/L indicates a 99% probability of GH deficiency 2
• An IGF-1 standard deviation score (SDS) of <-3 in adults over age 28 strongly suggests GHD, though even lower values are needed for diagnosis in younger adults 2
• IGF-1 assay provides good discrimination between GHD and normal subjects up to age 40, but becomes less reliable as a standalone test in older adults 2, 3
• In children and adolescents, severe primary IGF-1 deficiency (SPIGFD) is defined as basal IGF-1 SDS ≤-3 with normal or elevated GH levels, indicating GH resistance 4

Secondary Causes of Low IGF-1

Before attributing low IGF-1 to GHD, exclude these common secondary causes 2:

• Malnutrition and energy deficiency: Low energy availability directly suppresses hepatic IGF-1 production 1
• Severe hypothyroidism: Thyroid hormone is required for normal IGF-1 synthesis 1
• Liver disease: IGF-1 is synthesized primarily in the liver; hepatic dysfunction reduces production 1, 2
• Poorly controlled diabetes mellitus: Hyperglycemia and insulin resistance impair IGF-1 generation 1
• Renal failure: Chronic kidney disease causes GH resistance and reduced IGF-1 bioactivity 1
• Severe infection: Acute illness suppresses the GH-IGF-1 axis 1
• Oral estrogen therapy: First-pass hepatic metabolism suppresses IGF-1 production and upregulates IGF-1 binding proteins (IGFBP-1), further reducing bioavailability 1, 5

Clinical Manifestations by Population

In Children and Adolescents

Low IGF-1 in the context of GH deficiency or resistance presents with 1:

• Growth failure with height SDS <-2 or growth velocity <-2 SDS
• Delayed bone age
• Delayed puberty
• Reduced muscle mass and increased adiposity

In Amenorrheic Athletes

Low IGF-1 is a critical marker of energy deficiency in the Female Athlete Triad 1:

• Reflects inadequate energy availability relative to exercise expenditure
• Contributes directly to impaired bone health and low bone mineral density (BMD)
• Associated with functional hypothalamic amenorrhea (FHA)
• Oral contraceptive pills further suppress already-low IGF-1 levels in these athletes, limiting bone health benefits 1

In Adults with Chronic Medical Disorders

• Low IGF-1 occurs independently of other anterior pituitary hormone deficiencies (LH, FSH, TSH) in 9-20% of patients with chronic medical conditions 6
• IGF-1 deficiency between 84-100 μg/L may be too high a threshold for diagnosing adult GH deficiency in the context of chronic illness 6
• In obesity, despite reduced GH secretion, IGF-1 levels are only slightly reduced due to compensatory hyperinsulinism 3

Physiological Context

IGF-1 Regulation and Bioavailability

• IGF-1 is secreted by the liver in response to GH and produced locally in target tissues (bone, muscle) in an autocrine manner 1, 5
• Approximately 98% of circulating IGF-1 is bound to six insulin-like growth factor binding proteins (IGFBPs), which modulate its bioavailability 7
• Ten additional IGFBP-related proteins (IGFBP-rPs) bind IGF-1 with lower affinity 7
• This extensive protein binding significantly complicates IGF-1 measurement and interpretation 7

Age-Related Changes

IGF-1 levels progressively decrease with age in normal subjects 2, 3:

• 3rd decade: median 230 μg/L (3rd percentile: 108.6 μg/L)
• 4th decade: median 220 μg/L (3rd percentile: 129.8 μg/L)
• 5th decade: median 150.5 μg/L (3rd percentile: 72.4 μg/L)
• 6th decade: median 163.0 μg/L (3rd percentile: 62.4 μg/L)
• 7th decade: median 110 μg/L (3rd percentile: 41.6 μg/L)
• 8th decade: median 82 μg/L (3rd percentile: 24.7 μg/L) 3

Critical Pitfalls to Avoid

1. Do not diagnose GHD based solely on low IGF-1 without dynamic GH testing in most clinical scenarios 2
2. Always use age-matched, sex-matched, and Tanner stage-matched reference ranges specific to your laboratory's assay 1
3. In amenorrheic athletes, do not prescribe oral contraceptives to "treat" low IGF-1 or bone health—this further suppresses IGF-1 and does not improve BMD 1
4. Recognize that IGF-1 levels can be falsely normal in early GH excess or falsely low despite adequate GH in conditions of GH resistance 1
5. Inter-assay variability is substantial; confirm abnormal values with repeat testing at least one month apart 1

Management Implications

When Low IGF-1 Reflects True GHD

• Recombinant human GH therapy increases IGF-1 levels, lean body mass, and normalizes cardiac performance in confirmed GHD 5
• In severe primary IGF-1 deficiency with GH resistance, recombinant human IGF-1 (mecasermin) is the treatment of choice 4
• In anorexia nervosa with low IGF-1, rhIGF-1 combined with transdermal (not oral) estrogen increased BMD by 2.8% in RCT 1, 5

When Low IGF-1 Reflects Energy Deficiency

The priority is restoring energy availability through increased caloric intake and/or reduced exercise expenditure, not pharmacological intervention 1:

• Nutritional intervention normalizes gonadotropin pulsatility and IGF-1 production
• Weight gain correlates more strongly with BMD improvement than hormonal therapy
• Resumption of menses is the key clinical marker of successful treatment